POS0148 STIFFNESS INDUCED PROGRESSION OF FIBROSIS BY SORBIN AND SH3 DOMAIN-CONTAINING PROTEIN2 IN SYSTEMIC SCLEROSIS
Authors: A. Soare, Y. Ariza, S. Weber, S. Rauber, C. G. Anchang, H. Mohammadian, M. G. Raimondo, J. Distler, G. Schett, A. Ramming
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Persistently activated fibroblasts status leads to progressive extracellular matrix (ECM) deposition and tissue remodeling. The hallmark of systemic sclerosis (SSc) is collagen accumulation in organs, mainly in skin and lung. Despite intensive progress in understanding disease occurence, SSc remains an intriguing disease with unknown pathology and high mortality. Sorbin and SH3 domain-containing protein2, encoded by SORBS2 is a key member of the sorbin homology family of adapter and scaffold proteins. Recent studies suggest that SORBS2 plays a role in cardiac disease, however there is no available data about its role in fibrotic conditions. <h3>Objectives</h3> We aimed to investigate the role of SORBS2 in the pathogenesis of SSc. <h3>Methods</h3> To identify molecules specifically upregulated in persistently activated fibroblasts, human fibroblasts were chronically stimulated with TGF-β and analyzed by RNA-sequencing. To evaluate the functional implication of tissue elasticity on the transcriptome of fibroblasts, multiwell stiffness assays were performed. SORBS2 expression was further analyzed in skin samples of patients with SSc and murine models of fibrosis. Fibroblast specific SORBS2 knockout mice were challenged with bleomycin to induce skin and lung fibrosis. Further specific readouts like collagen content, skin thickness, myofibroblast count, CT scans were performed. <h3>Results</h3> Upon chronic TGF-β stimulation of human normal skin fibroblasts we identified SORBS2, as significantly upregulated molecule. SORBS2 is implicated in cytoskeletal organization, cell adhesion and different signaling pathways. Moreover, extracellular stiffness induced upregulation of SORBS2 mRNA level in fibroblasts. Deletion of SORBS2 in fibroblasts led to a change of the diameter of collagen fibers and modified the elastic index of the tissue. SORBS2 expression is not only elevated in different animal models of fibrosis, but also in fibrotic skin samples of SSc patients. SORBS2 knockout mice (KO) developed significantly less skin fibrosis upon bleomycin challenge in comparison to wild type mice (WT), as assessed by measurement of dermal thickness, myofibroblast counts and hydroxyproline content. <i>Col1a1</i>, <i>Col1a2</i> and expression of <i>αSMA</i> were significantly lower in SORBS2 KO mice in comparison to SORBS2 WT mice. Similarly, fibroblast specific knockout of SORBS2 showed protective effects in bleomycin induced lung fibrosis. CT scans of the lungs showed statistically significant less fibrotic changes in SORBS2 KO mice in comparison to wild type mice. <h3>Conclusion</h3> SORBS2 is engaged in a vicious circle of fibrosis. Triggered by chronic TGF-β stimulation, SORBS2 is further upregulated by the increasing stiffness of the extracellular matrix. This leads to persistently high levels of SORBS2 resulting into further production of ECM products. Deleting SORBS2 has potent antifibrotic effects in animal models of skin and lung fibrosis. As most of the currently used therapeutic approaches are focussed on early stages of the disease, SORBS2 might be an interesting new therapeutic target in established stages of SSc. <h3>REFERENCES:</h3> NIL. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> None Declared.